Shigellosis is a severe diarrheal disease caused by infection by bacteria of the genus Shigella. Shigellosis is associated with high morbidity and mortality rates, particularly in the developing world. It is also responsible for long-term effects on cognitive and physical development in children. The global burden has been estimated at more than 160 million cases per year; the most affected being children under 5 years of age living in endemic areas. The causative agent can be transmitted from person to person through fecal-oral contact or through contaminated fomites; ingestion of as few as 10 organisms can cause illness in adult volunteers. In industrialized countries, Shigella is known to be responsible for cases of pediatric diarrhea and to cause occasional foodborne outbreaks. Other susceptible groups include travelers, military personnel and refugees. Additionally, the Centers for Disease Control and Prevention lists Shigella as a food safety threat.
The Shigella genus comprises four different species: Shigella dysenteriae, Shigella flexneri, Shigella sonnei and Shigella boydii. These organisms are further divided into multiple serotypes, based on the structure of the O-polysaccharide portion of their outer membrane lipopolysaccharide (LPS), thereby increasing their antigenic variability. One serotype in particular, S. dysenteriae serotype 1, which produces Shiga toxin, is responsible for the most severe infections, including hemolytic uremic syndrome and it is the cause of epidemic dysentery. Additionally, serotypes can drift during outbreaks, further limiting the efficacy of vaccines that are restricted to particular serotypes. The emergence of strains resistant to antimicrobial drugs, including ciprofloxacin, currently the first-line antibiotic treatment against Shigella infections, heightens the difficulty of controlling this pathogen and makes the development of an effective vaccine even more urgent.
Despite being a longstanding priority for the World Health Organization, and the progress made in recent years, no licensed vaccine for Shigella spp. currently exists. Efforts to develop a vaccine against this pathogen have included the use of killed bacteria, live attenuated and recombinant carrier organisms, polysaccharide conjugates and LPS/protein mixtures. When tested in humans, these vaccines were either too reactogenic or poorly immunogenic. A major disadvantage of these candidates is the O antigen restriction, which limits the scope of protection they can offer and requires the development of a multi-serotype vaccine to provide adequate protective coverage in Shigella endemic areas.
The type III secretion system (TTSS) is a common virulence mechanism in many Gram-negative pathogens. Resembling a molecular needle and syringe, the TTSS apparatus provides a conduit for the translocation of effector proteins from the bacterial cytoplasm to the host cell cytoplasm. Residing atop the TTSS needle tip is a tip complex composed of IpaB and IpaD sequentially assembled, which is required for pathogenesis. Several studies have reported the presence of antibodies against Ipa proteins in serum from infected individuals, in subjects immunized with live attenuated organisms during clinical trials and following vaccination in animal models. The conserved nature of the IpaB and IpaD and their critical role in pathogenesis make them ideal targets for vaccine development. An Ipa-based vaccine would provide broader coverage across multiple serotypes. It would also simplify vaccine production and formulation.